The growing demand for chiral non-racemic compounds and drugs in the pharmaceutical industry has created a formidable synthetic challenge for chemists to find cost-effective and highly stereoselective means to assemble these molecules. Of the various methods available for the preparation of enantiomerically pure compounds, asymmetric catalytic processes are the most attractive. Over the past several decades, the main body of research in catalysis has been focused on transition metal-based organometallic catalysts and significant progress has been made. Surprisingly, however, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts (organocatalysts) despite their enormous potential in asymmetric transformations and widespread availability in optically pure forms.
A chiral molecule is one that is not superimposable on its mirror image. Often referred to as “handedness,” (in fact the term “chirality” derives from the Greek word for “hand”) since the property can be demonstrated by examining one's hands, which are mirror images of each other, but which are not superimposable one on the other. A chiral molecule is also observable for having the property of rotating the plane of polarization of plane-polarized monochromatic light passed through it—a phenomenon called “optical activity.” Pure solutions of a single stereoisomer (the chiral molecule and its mirror image are called “stereoisomers” or “enantiomers”) will rotate the plane of plane polarized light in one direction, and the other enantiomer will rotate polarized light the same number of degrees, but in the opposite direction. For this reason, stereoisomers are often called “optical isomers.” A solution that contains an equal mixture of the two optical isomers (a “racemic” mixture) will not change the plane of plane polarized light, because the effects of the two isomers cancel each other out. Pairs of stereoisomers are sometimes indistinguishable one from another in chemical reactions, but can be distinguished by examining a physical property (usually optical) of the molecule.
It has long been known, particularly in the pharmaceutical industry, that often one enantiomer is more effective in a reaction (or in a therapeutic treatment) than its mirror-image counterpart. In fact, in one well documented case of the importance of chirality, the use of a racemic mixture of thalidomide in pregnant women caused severe birth defects in their children. It was determined that one enantiomer was a powerful sedative while the other was toxic. As a result, obtaining a substantially pure form of a single enantiomer is often very desirable.
Given the Laws of Thermodynamics, this proves initially difficult. The left- and right-handed forms have identical free energy (G), so the free energy difference (ΔG) is zero. The equilibrium constant for any reaction (K) is the equilibrium ratio of the concentration of products to reactants. The relationship between these quantities at any Kelvin temperature (T) is given by the standard equation:K=exp(−ΔG/RT)
wherein R is the universal gas constant (Avogadro's number×Boltzmann's constant k)=8.314 J/K·mol.
For the reaction of changing left-handed to right-handed amino acids (L→R), or the reverse (R→L), ΔG=0, so K=1. That is, the reaction reaches equilibrium when the concentrations of R and L are equal; that is, a racemate is produced.
For separation of or “resolving” a racemate (i.e., separate the two enantiomers), another homochiral substance is usually introduced. The idea is that right-handed and left-handed substances have identical properties, except when interacting with other chiral phenomena. The analogy is that our left and right hands grip an achiral (non-chiral) object like a stick equally, but they fit differently into a chiral object like a left-handed glove. Thus to resolve a racemate, an organic chemist will usually use a ready-made homochiral substance from a living organism. The reaction products of the R and L enantiomers with an exclusively right-handed substance R′, that is R-R′ and L-R′ (called diastereomers), are not mirror images. So they have different physical properties, e.g. solubility in water, and thus they can be separated.
The trick here is that you have to have the homo-chiral substance to separate the enantiomers and be able to separate the substance from the desired enantiomer. While available for separation of some chiral substances, such substances are certainly not readily available for all. Chemists have tried other ways to reach their goal of substantially pure enantiomers, including asymmetric synthesis, wherein only one enantiomer is produced in synthesis of the compound, thereby eliminating the need to resolve a racemate.
In particular, asymmetric synthesis of optically active natural and unnatural α-amino acids has been of long-standing interest to organic chemists since these substances are versatile synthetic building blocks for the preparation of an assortment of biologically important molecules. In this regard, the enantioselective Mannich-type reaction of an enolate or enolate equivalent with α-imino ester constitutes a powerful approach to the synthesis of novel functionalized γ-keto-α-amino acid derivatives. S. E. Denmark, O. J.-C. Nicaise In Comprehensive Asymmetric Catalysis, (Eds.; E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, pp 926; b) D. Arend, B. Westermann, N. Risch, Angew. Chem. 1998, 110, 1096-1122; D. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
Over the past few years, catalytic, enantioselective versions of this process have received great attention with emphasis being given to the development of organometallic catalysis. S. E. Denmark, O. J.-C. Nicaise In Comprehensive Asymmetric Catalysis, (Eds.; E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Heidelberg, 1999, pp 926; b) D. Arend, B. Westermann, N. Risch, Angew. Chem. 1998, 110, 1096-1122; D. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998, 37, 1044-1070; H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997, 119, 7153-7154; b) S. Kobayashi, T. Hamada, K. Manabe, J. Am. Chem. Soc. 2002, 124, 5640-5641; c) H. Ishitani, S. Ueno, S. Kobayashi, J. Am. Chem. Soc. 2000, 122, 8180-8186; E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998, 120, 2474-2475; b) A. Fujii, E. Hagiwara, M. Sodeoka, J. Am. Chem. Soc. 1999, 121, 545-556; D. Ferraris, B. Young, T. Dudding, T. Lectka, J. Am. Chem. Soc. 1998, 120, 2474-2475; b) D. Ferraris, B. Young, C. Cox, T. Dudding, W. J. Drury, III, L. Ryzhkov, T. Taggi, T. Lectka, J. Am. Chem. Soc. 2002, 124, 67-77.
However, these metal-based catalysis methods rely on the use of pre-formed enolates or enolate equivalents. An effective, atom-economic asymmetric version of this reaction, employing unmodified carbonyl compounds would be more attractive from a synthesis standpoint. The examples of such reactions catalyzed by organometallic-based chiral catalysts have been described by Shibasaki, Trost and Jørgensen. S. Yamasaki, T. Iida, M. Shibasaki, Tetrahedron Lett. 1999, 40, 307-310; B. M. Trost, L. M. Terrell, J. Am. Chem. Soc. 2003, 125, 338-339; K. Juhl, N. Gathergood, K. A. Jørgensen, Angew. Chem. 2001, 113, 3083-3085; K. Juhl, N. Gathergood, K. A. Jørgensen, Angew. Chem. Int. Ed. 2001, 40, 2995-2997.
The development of metal-free organo-catalysts has emerged as a new frontier in asymmetric catalysis, pioneered by List, Barbas III, and MacMillan. P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840-3864; P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40, 3726-3748; b) a review of proline catalyzed reactions: B. List, Tetrahedron 2002, 58, 5573-5590; B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000, 122, 2395-2396; K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243-4244.
Several catalytic systems including L-proline, peptides and small organic molecules have been reported for the Mannich reactions. B. List J. Am. Chem. Soc. 2000, 122, 9336-9337; B. List, P. Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124, 827-833; Y. Hayashi, W. Tsuboi, M. Shoji, N. Suzuki, J. Am. Chem. Soc. 2003, 125, 11208-11209; Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. 2003, 115, 3805-3808; Y. Hayashi, W. Tsuboi, I. Ashimine, T. Urushima, M. Shoji, K. Sakai, Angew. Chem. Ed. Engl. 2003, 42, 3677-3680; A. Córdova, W. Notz, G. Zhong, J. M. Betancort, C. F. Barbas III, J. Am. Chem. Soc. 2002, 124, 1842-1843; b) A. Córdova, S. Watanabe, F. Tanaka, W. Notz, C. F., Barbas III, J. Am. Chem. Soc. 2002, 124, 1866-1867; c) A. Córdova, C. F. Barbas III, Tetrahedron Lett. 2003, 44, 1923-1926; P. Vachal, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 10012-10013; b) A. G. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964-12965. Only the L-proline catalyzed process described by Barbas III (referenced above) and his co-workers promotes direct Mannich-type reactions of ketones and aldehydes with α-imino esters.
Compared with traditional metal-ligand complex catalysts, it is surprisingly found that metal-free organo-catalysts are less expensive, benign to the environment, easy to prepare and handle, and are air-stable, and non-sensitive to moisture. Therefore, the field would be greatly enhanced with the development of novel metal-free organo-catalysts which reduce time, effort, and amount of reactant necessary to arrive at a single enantiomer product. In turn, industries such as the pharmaceutical industry which require such purified forms can reduce the cost of and improve the quality of their ultimate product.
Over 50 percent of all drugs on the world market are based on chiral molecules and their sales exceeded $159 billion in 2002.[1-3] The Food and Drug Administration requires that both enantiomers of new chiral drugs are fully characterized separately with respect to pharmacological activity, iii vitro and in vivo pharmacokinetic profile, and toxicology. Consequently, most chiral pharmaceuticals will be sold as enantiomerically pure forms. This has created a great demand for chemists to develop new methodologies and strategies for efficient and enantioselective synthesis of chiral non-racemic compounds and drugs. Of the various methods available for the preparation of enantiomerically pure compounds, asymmetric catalytic processes are the most attractive.[4, 5] New and effective catalytic reactions have been discovered at an explosive rate. While the field is progressing rapidly, many challenges remain in asymmetric catalysis. Developing highly active catalysts that feature broad substrate scope and that can function under mild and simple reaction conditions remains a critical issue. Moreover, with the increasing environmental concerns associated with massive production of chemical wastes and hazards, the synthesis of chemicals, therapeutic agents and materials in an efficient, practical, economical, and environmentally benign fashion poses a paramount challenge to organic chemists.[6] It is especially important to identify reactions that are based on readily available starting materials and reagents utilizing environmentally benign chemical processes. [7-9]
Over the past 30 years, the major focus in catalysis has been directed towards the development of organometallics, which consist of metal complexes with chiral ligands and tremendous progress has been made.[4, 5] However, surprisingly, purely organic compounds, despite their enormous potential and broad availability in optically pure forms, are rarely used in asymmetric catalysis. In recent years, with the realization of this deficiency and inspired by enzyme-catalyzed reactions in biological systems, small organic molecule-based organocatalysts have gradually been recognized and emerged as a new frontier in asymmetric catalysis. [10-16] It has been demonstrated that, in many cases, these small molecule catalysts display high catalytic activities for organic reactions that proceed with excellent enantio- and/or diastereoselectivities. Compared with their counterpart organometallic catalysts, these substances afford distinguishable benefits. First, they are easily prepared, more environmentally benign and cheaper since they do not rely on expensive and toxic metals. Second, generally organocatalysts catalyzed reactions can be performed under an aerobic condition in common, even water-containing organic solvents. Third, they are more robust and can be stored and handled in an air atmosphere, thus providing operational simplicity. Fourth, these small organic molecules can be immobilized on a solid support and reused more conveniently than are organometallic/bioorganic analogues. Consequently, they show promising adaptability to high-throughput screening and process chemistry. Other advantages associated with the use of organocatalysts, especially compared with enzymes and other bioorganic catalysts, are that they are more stable and less expensive and that they are capable of catalyzing a variety of organic reactions with a diverse range of different substrates.
Despite early successes in study of asymmetric organic transformations catalyzed by amino acid proline as a representative organocatalyst, relatively few efficient organocatalysts other than amino acid have been developed.[10, 12, 13, 17-19] Therefore, in the new emerging field, there are many opportunities for innovation and considerable challenges exist for the development of novel organocatalysts. In this proposal, we describe a novel “privileged” structure-based approach for catalyst design that should lead to a new class of organocatalysts. Such catalysts can provide high levels of asymmetric induction across a broad spectrum of chemical processes. This strategy has been very successfully employed in drug design and development by utilization of a “privileged” structure as a platform to which different functionality is added to produce a number of potent and specific drugs or drug candidates towards different therapeutic targets.[20-22] Such an approach can be employed in both the conceptual and practical development of new organocatalysts. The benefits of this strategy are not only found in a new paradigm for catalyst development, but also in the realization of high catalytic efficiencies that afford broad substrate scopes for a variety of organic transformations.
In the design of novel organocatalysts by using a “privileged” structure-based approach, the selection of the “privileged” core scaffolds is critical to the success of catalyst development. A careful survey of successful organocatalysts, including the amino acid proline,[12-14] MacMillan[23-29] and Jorgenson's catalysts[30-33] and others,[15, 34-41] reveal that a five-membered ring system containing a nitrogen atom is essential for catalytic activity.
The advantages, objects and features of such stereo-selective catalysts will become apparent to those skilled in the art when read in conjunction with the accompanying following description and drawing figures. As those skilled in the art will appreciate, the conception on which this disclosure is based readily may be used as a basis for designing other structures, methods, and systems for carrying out the purposes of the present invention. The abstract associated with this disclosure is neither intended to define the invention, nor intended to be limiting as to the scope of the invention in any way.